Obesity is a hyperlipidemic state characterized by excessive adipose tissue that often leads to diabetes and osteoporosis. Glucocorticoid receptor-? (GR?) and peroxisome proliferator-activated receptor-? (PPAR?) are members of the nuclear receptor family that are essential to adipocyte differentiation and function. In general, GR? and PPAR-? can be viewed as physiologic antagonists, with GR promoting lipolysis at adipose tissue, but PPAR-? promoting adipogenesis and lipid storage. Moreover, each receptor is regulated by phosphorylation, but in opposite ways: stimulatory to GR?, but inhibitory to PPAR-?. We have recently shown that two nuclear receptor chaperones, protein phosphatase 5 (PP5) and the FK506-binding protein-51 (FKBP51), can reciprocally regulate the molecular and metabolic activities of GR? and PPAR-? through phosphorylation. PP5 dephosphorylates GR at multiple serines to decrease its lipolytic activity, while dephosphorylating PPAR? at serine 112 to increase its adipogenic and lipid storage actions. Thus, PP5 can be viewed as a pro-lipogenic, anti-lipolytic factor. Our studies in PP5-KO mice support this view since the mice have greatly reduced whole body fat, including low lipid content in marrow fat cells and increased bone density. Interestingly, the PP5-KO mice also have increased insulin sensitivity and energy expenditure. The latter features suggest increased PPAR? insulin-sensitizing activity in the null mice ? actions known to be inhibited by CDK5-mediated phosphorylation at S273 of the receptor. Our latest data suggest that PP5 increases PPAR? S273 phosphorylation by dephosphorylating and activating the p35 regulatory subunit of CDK5. Thus, PP5 may inversely control the lipogenic and insulin sensitizing actions of PPAR? by directly dephosphorylating the receptor at S112 and indirectly phosphorylating the receptor at S273 by activating CDK5. We have shown that FKBP51 also negatively regulates GR? and positively regulates PPAR?, but it does so by inhibiting the Akt-p38 kinase pathway, leading to decreased phosphorylation of PPAR? at S112 and GR? at serines 220 and 234. This results in FKBP51-KO cells that are also resistant to adipogenesis and lipid buildup and in FKBP51-KO mice with reduced adipose depots and increased bone mass. Interestingly, FKBP51-KO mice are resistant to high-fat diet effects on insulin sensitivity and resistant to the PPAR-? agonist rosiglitazone. In this application, we will test the overall hypothesis that PP5 and FKBP51 are pro-adipogenic, pro-osteoporotic and pro-diabetic factors that act in adipose tissue by differentially targeting GR? and PPAR-? via phosphorylation. Thus, each chaperone may represent an ideal inhibitory drug target for obesity, osteoporosis and diabetes through the dual effect of inhibiting lipogenesis/osteoporosis but promoting anti-diabetics activities. This will be tested in molecular and cellular assays to further define the roles of the CDK5 and Akt-p38 kinase pathways in regulation of each receptor, and by directly testing the relevance of these kinase pathways to receptor effects on metabolism and bone density in both null and adipose-specific knock out mice.